Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Histopathology of Sclerotinia sclerotiorum attack on flower parts of Helianthus annuus heads in tolerant and susceptible varieties

Sunflower head rot is a major disease caused by Sclerotinia sclerotiorum. Sunflower varieties which are tolerant to the fungus have been developed. The changes occurring in flower parts at different times after inoculation with pathogen ascospores were studied for two sunflower varieties (tolerant HA 302 and susceptible HA 89). In variety HA 302 there was cell collapse, changes in cell wall composition, and an increase in phenolic compounds in the tissues of corolla and style, which prevented the pathogen from advancing. This response was weaker in susceptible variety HA 89, and occurred only in the style, so did not stop the pathogen from developing and reaching the ovary. Phenolic compounds were found in HA 302 corolla and style tissues only when the pathogen was present, constituted an induced response that prevented further development of the fungus. Principal component analysis (PCA) showed that at the beginning of the infection there was no difference in behavior between the two varieties. The difference arose during the final observation times, when in variety HA 89, the pathogen colonized ovary, style and base of filaments and produced noticeable colonization of the corolla.Fil: Rodríguez, M. A.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental; ArgentinaFil: Venedikian, Nadia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental; ArgentinaFil: Bazzalo, M. E.. No especifíca;Fil: Godeas, Alicia Margarita. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Biodiversidad y Biología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; Argentin

First Report of Diaporthe gulyae Causing Phomopsis Stem Canker of Sunflower (Helianthus annuus) in Argentina

Between 2014 and 2017, elongated, brown lesions were observed on the stem and heads of sunflower (Helianthus annuus L.) plants in the Argentine Southern Sunflower Region (ASSR). A total of 66 diseased plants (40 stems and 26 heads) were sampled from the three production fields: Balcarce (37°52′36.6″S; 58°15′29.4″W; 19 samples), Orense (38°41′36.3″S; 59°47′01.9″W; 36 samples), and Pieres (38°23′31.2″S; 58°40′22.8″W; 11 samples). Fungal isolations were made from the lesion margins of the stem and head by cutting, surface disinfesting, and plating tissue pieces on potato dextrose agar (PDA) amended with 0.02% lactic acid (pH 4.5). The PDA plates were incubated at 25°C for 7 to 10 days under a 12-h photoperiod, and hyphal tips of white to gray colonies were transferred to fresh PDA plates

Six species of Diaporthe associated with Phomopsis stem canker of sunflower in southern Pampean region of Argentina

A survey of 67 commercial fields in 19 locations was conducted in the southern Pampean region of Argentina for Phomopsis stem canker of sunflower (Helianthus annuus L.) between 2014 and 2019. A total of 210 plants having typical symptoms of Phomopsis stem canker were randomly sampled, and fungal isolation was performed. Of the 187 isolates of Diaporthe that were recovered, 94% of the isolates showed morphological characteristics similar to D. helianthi, 3% to D. gulyae, 1% to D. caulivora, 1% to D. sojae, 0.5% to D. kongii, and 0.5% to D. longicolla. Following morphological characterization, the identity of the six morpho-species was confirmed by phylogenetic analyses of b-tubulin, translation elongation factor 1-a, and internal transcribed spacer gene regions. Koch’s postulates were completed for the six fungi by inoculating one susceptible sunflower hybrid with one isolate each of the six species of Diaporthe using the stem-wound inoculation method. Seven days postinoculation, significant differences in disease severity were observed between the six isolates (P < 0.0001), with D. helianthi and D. gulyae isolates causing significantly greater disease severity. To our knowledge, this is the first report of D. kongii, D. longicolla, D. caulivora, and D. sojae associated with Phomopsis stem canker of sunflower in Argentina.Fil: Zambelli, Andres Daniel. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Mancebo, María F.. Advanta Semillas S.A.I.C.; ArgentinaFil: Bazzalo, María E.. Advanta Semillas S.A.I.C.; ArgentinaFil: Reid, Roberto J.. Advanta Semillas S.A.I.C.; ArgentinaFil: Sanchez, María C.. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Kontz, Brian J.. South Dakota State University; Estados UnidosFil: Mathew, Febina M.. South Dakota State University; Estados Unido

Report of the Working Group on Major Threats and Conservation

Report of the Working Group on Major Threats and Conservatio